Therapeutic composition and process



United States Patent THERAPEUTIC COMPOSITION AND PROCESS Jerry Pleyte, Robert E. Himelick, Kalamazoo, and Jack K. Dale, Kalamazoo Township, Kalamazoo County, Mich., assignors to The Upjohn Company, Kalamazoo, Mich, a corporation of Michigan No Drawing. Application October '28, 1957 Serial N0. 692,588

12 Claims. (Cl. 167-82) This invention relates to a medicinal tablet and to a process for its production and more particularly relates to a tablet containing an adrenocortical steroid hormone, calcium carbonate and acetylsalicylic acid in a special stable form and to a process for the production of such atablet.

Adrenocortical steroid hormones are now well-established therapeutic agents having a wide range of applications in the medical field. Cortisone, hydrocortisone and their more recently introduced analogues, for example, prednisone, prednisolone, and 6-methyl-prednisolone, have been found especially useful as systemic and topical anti-inflammatory agents. Thus, they have been used in the treatment of rheumatic diseases and allergies.

Acetylsalicylic acid, i.e. aspirin, is probably one of the best known of all therapeutic agents. Its usefulness extends all the way from treating simple headaches to treat-- ing such disabling diseases as rheumatism.

It is largely because both the corticosteroids and aspirin are useful in treating rheumatic diseases that it has been throught desirable to combine the two ingredients, particularly in an oral dosage form which is the most convenient form for administering the two drugs. Since both ingredients sometimes cause gastro-intestinal upsets when taken orally, it would also be desirable to include a butter in such an oral dosage form.

However, the actual preparation of such an oral dosage. form presented unusual and unexpected difficulties. Thus, when a simple compressed tablet, capsule or bulk powders of the above ingredients are prepared, the hormone is partially oxidized, the aspirin hydrolyzed, the buffer neutralized and a heavy gas pressure developed.

It is therefore an object of this invention to provide a pharmaceutically elegant buifered medicinal tablet containing an adrenocortical steroid hormone and acetylsalicylic acid. Other objects of the invention will be apparent to those skilled in the art to which this invention pertains.

The foregoing and additional objects have been accom-.

plished by the provision of a compression-coated medicinal tablet comprising an inner core section containing a mixture of an'adrenocortical steroid hormone and calcium carbonate and an outer layer surrounding said core section containing a member selected from the group consisting of acetylsalicylic acid and a compound yielding acetylsalicylic acid on hydrolysis. Such a tablet is prepared by a novel process comprising the addition of a powdered adrenocortical steroid hormone to previously granulated calcium carbonate, compressing the adrenocortical steroid hormone-calcium carbonate mixture to form the core section of the ultimate tablet, and surrounding said core section with a reciprocally bonded layer containing the acetylsalicylic compound. These steps should preferably be carried out under low humidity conditions with dried ingredients to provide a tablet having a water content of less than about 0.9 percent by weight. A tablet prepared by such aprocess possesses greater chemical stability of the hormone, greater chemical stability of the acetylsalicylic acid, greater buifer activity, greater physical stability, faster disintegration characteristics, and greater all-around pharmaceutical elegance than similar products available heretofore. Moreover, such a tablet has favorable size characteristics and lends itself easily to practical manufacturing requirements.

The term adrenocortical steroid hormone as used herein has reference to steroids of the adrenal cortex, e.g. cortisone and hydrocortisone and their therapeutically active derivatives and analogues. Typical derivatives include esters and ethers, especially the acetate ester. Typical analogues include prednisone, prednisolone, -methylprednisone, 6-methyl-prednisolone, 6-fiuoro-hydrocortisome and 6-fluoro-prednisolone. Derivatives of such analogues. e.g. the acetate ester, are also included.

The term compression-coated as used herein has reference to the method described in Remington, Practice of Pharmacy, Eleventh Edition, page 406, Mack Publishing Company, 1956.

Prior to the present invention it was not known how a stable composition containing an adrenocortical steroid hormone, an acetylsalicylic acid compound and calcium carbonate could be prepared. were intimately mixed or compressed as a single mixture, the acetylsalicylic acid would undergo hydrolysis with the production of undesirable acetic acid odor, salicylic acid formation and a pink coloration. Thus, when such a powder mixture containing 200 milligrams of calcium carbonate and 300 milligrams of acetylsalicylic acid was prepared, the acetylsalicylic acid underwent 7.38 percent hydrolysis after one year at room temperature (Method of analysis: Tinker and McBay, I.A.Ph. Assoc, Scientific Edition, 43, page 315, 1954). Such degradation is tremendously excessive as evidenced by the fact that the USP. limit for hydrolysis in acetylsalicylic acid tablets is only 0.15 percent. A simple compressed tablet of the above ingredients is even less stable since the hormone is partially oxidized, the aspirin hydrolyzed, the buffer neutralized (by liberated acetic acid) and a heavy gas pressure developed (by reaction of liberated acetic acid with calcium carbonate).

When the problem was first encountered, many procedures and dosage forms and combinations thereof were tried, but only the medicinal tablet and process of this invention satisfied all of the therapeutic and manufacturing requirements for a suitable commercial product. These requirements relate to ease of manufacture, stability of the active ingredients, size of finished dosage form, pharmaceutical elegance, and the like.

The arrangement of the active ingredients in the compression-coated tablet is critical. It is possible to arrange the three active ingredients in the ultimate tablet in several different Ways. The present invention comprising a core containing the steroid and calcium carbonate and a compression-coat containing. the acetylsalicylic acid compound has been found to be superior to the other possible arrangements because it meets satisfactorily the various problems concerned, i.e., ease of manufacture, size of the ultimate tablet, pharmaceutical elegance, buffering capacity, stability of the active ingredients, and the like.

For the preparation of the core component of the ultimate tablet, there is first prepared a granulation of calcium carbonate in the usual manner. The powdered steroid is then mixed into and blended with the calcium. carbonate granulation. This admixture of steroid and calcium carbonate is compressed to form the tablet core. Subsequently, said tablet core is coated uniformly with the acetylsalicylic acid compound by the technique known in the art as compressioncoating. This technique comprises controlled feeding to a compressing machine of the lower granulation charge of the acetylsalicylic If all of the ingredients a,ass,asa I f acid compound, perfect centering of the tablet core on and within the lower charge, controlled feeding of the upper granulation charge of the acetylsalicylic acid compound, and compressing simultaneously the lower and upper granulation charges around the tablet core. Precautions are exercised to maintain the moisture content of all ingredients, and the humidity of the surrounding atmosphere, at low levels consistent with maximum stability.

The active ingredients in the ultimate compressioncoated tablet can be varied over a range consistent with the practical limitations of oral tablet size and in harmony with the pertinent therapeutic indications. The usual dosage of acetylsalicylic acid, i.e. about 300 milligrams is preferred. However, from about 200 to about 400 milligrams can be utilized. The requirement of calcium carbonate is related to the amount of acetylsalicylic acid. Said requirement is met by an amount of calcium carbonate at least equimolar with the acetylsalicylic acid. It is preferred, however, to use more than the equimolar amount of calcium carbonate by about 100 milligrams to ensure neutralization and buffering of the gastric contents which are known to be normally acidic with a pH of approximately 1.0. The amount of adrenocortical hormone can vary from about 0.15 to about milligrams.

- Various supplementary and complementary active ingredients can be added to the composition of this invention. Muscle relaxants or tranquilizers, for example, meprobamate, 50 to 200 milligrams, reserpine, 0.25 to 1 milligram; analgesics, for example, codeine phosphate, 10 to 30 milligrams, acetophenetidin, 100 to 300 milligrams; antihistaminics, for example, chlorpheniramine maleate, 1 to 4 milligrams, pyrathiazine hydrochloride, 12.5 to 50 milligrams, and the like, can be added to the composition of the instant invention. For allergic conditions a particularly advantageous combination comprises a core of 6-methyl-prednisolone, 0.5 milligram, calcium carbonate, 200 milligrams, and chlorpheniramine maleate, 2 milligrams; the outer coat contains 300 milligrams of acetylsalicylic acid. In arthritic or rheumatic conditions, especially good results are obtained from a combination of 6-methyl-prednisolone, 0.3 to 1.5 milligrams and calcium carbonate, 200 milligrams in the core while the outer coat contains acetylsalicylic acid 300 milligrams and meprobamate 100 to 200 milligrams.

, Various secondary ingredients can be added to the composition of the instant invention. These secondary ingredients include disintegrators, for example, corn starch and potato starch; lubricants, for example, mineral oil and calcium stearate; diluents, for example, talc and sucrose; and binders, for example, methylcellulose and starch paste. Certified dyes can be used in the tablet core and in the outer coat.

The composition of the instant invention is useful in inflammatory and rheumatic affiictions susceptible to oral treatment and counteracts the gastric distress often associated with salicylate and adrenocortical steroid hormone therapy.

The first attempts to prepare a satisfactory pharmaceutical composition containing acetylsalicylic acid, buffer and adrenocortical steroid utilized the conventional technique of simple admixture of the various powdered ingredients. It was thought that an admixture of this type could be used as a bulk powder or filled into a telescoping capsule. It was discovered that such an admixture of powders was highly unstable. When placed in closed bottles or in capsules, the admixture developed a strong acetic acid odor and a distinct pink coloration. The U.S.P. permissible limits of acetylsalicylic acid hydrolysis were greatly exceeded. Moreover, a build up of gas pressure was found to occur in closed containers and in capsules containing the admixture.

Additional attempts to prepare a satisfactory pharmaceutical composition containing the three above types of active ingredients led to the preparation of a conventional compressed tablet. The difficulties and stability problems encountered with a simple powder admixture, as outlined above, were still present and in fact increased in that the steroid component deteriorated rapidly at 47 Centigrade, as shown in Table I.

The result was checked by a more accelerated stability test run at 70 degrees centigrade. After two days the initial content of the steroid of 1.5 milligrams per tablet had deteriorated to the level of only 0.55 milligram per tablet, showing that a storage-stable composition had not been obtained.

The failure of the recited attempts to prepare the subject composition in stable form led to the concept that interaction of the ingredients was causing the instabilities and that a novel method must be found for including the active ingredients in a single dosage form but at the same time preventing interaction by physical separation. Attempts were therefore made to utilize the technique hereinbefore defined as compression-coating. Numerous experimental procedures were followed in an endeavor to obtain maximum stability, satisfactory reciprocal-bonding and optimum ratio of active ingredients consistent with a pharmacetuically elegant and sizeacceptable ultimatetablet. All procedures failed to meet one or more of the desiderata until the composition and process of the invention were developed. Among the numerous experimental procedures the following are typical.

Series A.The tablet core contained prednisolone (1.5 milligrams) coated with ethylcellulose. The compression-coat was applied by compressing on the tablet core a mixture of an acetylsalicylic acid (300 milligrams) granulation and an aluminum hydroxide milligrams)-magnesium trisilicate (65 milligrams) granulation.

The reciprocal bonding action of the core and coat was insufiicient to guarantee a physically stable ultimate tablet. The ultimate tablet was too large for pharmaceutical elegance.

Reduction of the size of the ultimate tablet to satisfy pharmaceutical elegance failed in view of the continued absence of reciprocal bonding action between the tablet core and the compression coat.

Series B.-The tablet core contained 1.5 milligrams of prednisolone. The compression-coat was applied by compressing on the tablet core a mixture of an acetylsalicylic acid (300 milligrams) granulation and a calcium carbonate (100 milligrams)-magnesium oxide (100 milligrams) granulation.

The ultimate tablet was unsatisfactory because of excessive hydrolysis of the acetylsalicylic acid and deterioration of the adrenocortical steroid.

Coating of the tablet core with ethylcellulose did not improve sufficiently the acetylsalicylic acid stability.

Series C.The tablet core contained 1.5 milligrams of prednisolone, and acetylsalicylic acid. Only milligrams of acetylsalicylic acid could be included in the tablet core for compression-coating with a buffer mixture containing 150 milligrams of calcium carbonate and 150 milligrams of magnesium oxide. Increasing the acetylsalicylic acid to the required level of 300 milligrams and then applying the compression coat gave a tablet too large for pharmaceutical acceptability. Moreover, an

ultimate tablet with only 150 milligrams ofacetylsalicylie acid impaired the proper steroid-analgesic ratio.

Series D.The tablet core. contained 1.5 milligrams of prednisolone. The compression coat was applied by compressing on the tablet core a mixture of an acetylsalicylic acid (300 milligrams) granulation and a calcium carbonate (200 milligrams) granulation. The gross, ap-- pearance appeared satisfactory but the reciprocal bonding action between the tablet core and. the. compression-. coat was unsatisfactory.

Coating of the tablet core with ethylcellulose did not improve the reciprocal bonding action sufiicicntly to guarantee physical stability.

Series E.An attempt was made to prepare a tablet core of prednisolone (1.5 milligrams) and acetylsalicylic acid (300 milligrams) with a compression-coat of calcium carbonate (200 milligrams). However, only 162 milligrams of'acetylsalicylic acid could be incorporated with the prednisolone in said tabletcore because of greatly increased core dimensions with the full 300 milligrams. It required about 400 milligrams of calcium carbonate to complete the ultimate tablet, thereby rendering inoperative the buffer to acetylsalicylic acid, ratio.

Series F.--The tablet core contained 1.5 milligrams of prednisolone. The compression-coat contained acetylsalicylic acid (240 milligrams) and aluminum hydroxide (160 milligrams). In addition to excessive acetylsalicylic acid hydrolysis the ultimate tablet was unsatisfactory in not possessing the required reciprocal bonding action between the tablet core and the compression-coat.

Although the tablet core was coated with ethylcellulose and the compression-coat applied as outlined the required reciprocal bonding action between the core and coat was not obtained.

Series G.--The tablet core contained calcium carbonate (200 milligrams). The compression-coat con-. tained 1.5 milligrams of prednisolone and acetylsalicylic acid (300 milligrams). Although the reciprocal bonding action of the core and the coat was satisfactory, excessive hydrolysis of the acetylsalicylic acid occurred accompanied by deterioration of the adrenocortical steroid.

Series H .The tablet core contained 1.5 milligrams of prednisolone and calcium carbonate (200 milligrams). The compression-coat contained acetylsalicylic acid (300 milligrams). The ultimate tablet appeared to be satisfactory by all criteria until deterioration of the prednisolone was detected. vThis deterioration led to the discovery that the method of preparation of the prednisolone and calcium carbonate was critical. The technique ofgranulating the adrenocortical steroid with the calcium carbonate, which is optimum from manufacturing considerations, resulted in an ultimate tablet subject to steroid deterioration. However, adding the prednisolone as a powder to previously granulated calcium carbonate resulted in an ultimate tablet meeting all the stability and pharmaceutical criteria.

The following examples are illustrative of the processes and products of this invention, and are not to be construed as limiting.

EXAMPLE 1 Preparation of table! cores Each core contains: Mixture, Part I-200 milligrams calcium carbonate U.S.P.

dense, bolted Paste for granulating Part I-- Starch bolted, 1 part Syrup 50 percent, 3 parts Deionized water, 6 parts Mixture, Part II 0.5 milligram prednisolone 6.0 milligrams starch bolted 9.0 milligrams talc bolted Lubrication1.6 milligrams white mineral oil U.S.P., i viscosity 180 Directions- 'lhe mixture, Part-I, is granulated with q.s. starch-syrup paste and dried at to degrees Fahrenheit for twenty hours. The prednisolone is bolted with some-of the starch through number 9 cloth (100 mesh) andmixed with-the balance of the; starch and talc. The mineral oil issprayed onthe-dried granulated Part I in a lubricatingtub. The mixture, Part II, is added and the whole stirred well. The lubricated mixture of Part, I and Part; II is; slugged; and the. slugs broken up by forcing through anumber:1"2 screen. The, screened material is restirred in-thelubricating tub, and, compressed into the tablet cores, A;ll processing is carried. out. at a; relative humidity of less, thanv aboutforty percent.

e at a) co e sriem qeted; tablet These compression-coated tablets are assayed forv moisture, calcium. carbonate, prednisolone. and acetylsalicylic acid, and used clinically with satisfactory results.

EXAMPLE.

Using the procedure of Example 1, compression-coated tablets are prepared containing 0.5 milligram of predni solone per tablet in place of the 1.5 milligrams ofExample 1. These tablets are assayed for moisture, calciumcarbonate, prednisolone and acetylsalicylic acid, and used clinically with satisfactory results.

EXAMPLE 3 Using the procedureof Example 1, compression-coated tablets are prepared with a compression-coat. containing; from about 200 to about 400 milligrams ofacetylsalicylijcj acid, and a, tablet core containing from about 0.25toabout, 5 milligrams of prednisolone and 100 rnilligrams' of calcium carbonate in excess ofthe amount equirnolar with said acetylsalicylic acid.

EXAMPLE 4v Following the procedure of Example 1, compressioncoated tablets are prepared from a tablet core containing, in place of the prednisolone of Example 1, cortisone acetate from about 2.5 to about 25 milligrams; hydrocortisone acetate, from about 2 to about 20 milligrams; prednisone, from about 0.25 to about 5.0 milligrams; 6-methylprednisolone, from about 0.15 to about 4 milligrams; 6-fiuoro-hydrocortisone, from about 0.15 to about 4 milligrams; and 6-fluoro-prednisolone, from about 0.15 to about 4 milligrams.

EXAMPLE 5 Following the procedure. of Example. 1, exceptforthe. substitution of the acetylsalicylic apid by [acetylsalicylic acidl-anhydride, compression-coated tablets are prepared from a core containing 1.5 milligrams Of prednisolone and. 200 milligrams of calcium carbonate, with a coating of 300 milligrams of [acetylsalicylic acidl-anhydride. The. latter compound yields acetylsalicylic acid on gradual hydrolysis. 5

EXAMPLE 6 Following the procedure of Example 1', except for the '7 substitution of prednisolone by 6-methyl-prednisolone, compression-coated tablets are prepared, each containing 0.35 milligram of 6-methyl-prednisolone and 1.0 milligram of G-methyI-prednisolone, respectively. These tablets are assayed for strength of the active ingredients and used clinically with satisfactory results.

EXAMPLE 7 TABLE I Time A B O D Percent Percent Percent Percent 100 100 100 100 97 94 95 94 94 90 89 88 90 81 77 78 80 hours 87 72 64 65 These data show the marked superiority of A, i.e., the

composition of the invention, over B, C, and D, i.e., other similar commercially available products.

Table II contains the data on acetylsalicylic acid hydrolysis from comparative, accelerated tests run on four products at 70 degrees centigrade in sealed containers.

TABLE II Time A-l B-1 A-2 13-2 Percent Percent Percent Percent Start .0 3.5 0.0 3. 5 0. 6 8.0 1. 7 7. 9 1. 7 12. 8. 0 12. 0 60 hours 5. 0 18.0 15.0 18.0

These data show that A-1 and A-2, i.e., the composition of the invention are significantly more resistant to acetylsalicylic acid hydrolysis than B-1 and 3-2, i.e., other similar commercially available products.

Table III contains the data from tests on gas formation from seven compression-coated tablets of each of two products stored at seventy degrees centigrade in sealed containers.

TABLE III Time A I B Cc. Cc. Start 0 0 20 hours v 0 0.5 40 hours 0. 2 v 2.

These data show the significantly slower gas production, from deterioration of the ingredients in product A, i.e., the composition of the invention, than in product B, a similar commercially available product. It should be noted that the first appearance of gas formation is indicative of ingredient deterioration.

Table IV contains the comparative data on pH titration of whole compression-coated tablets by the method of Pale and Booth,-J. A. Ph. Assoc., Sci. Ed, 44, page 170,

1955. In this method one whole tablet is tested in simu: lated gastric juice (pH 1.0) at 37 degrees centigrade.

TABLE IV Time A B C l. 0 1. 0 1. 0 1. 6 1. 0 1.03 1. 8 1. 02 1. 1 1. 35 O. 1. 1 1. l5 0. 9 1.0

These data show that product A, i.e., the composition of the invention possesses faster and superior buffering power to products B and C, i.e., other similar commercially available products.

Although the composition and method of the instant invention provide a compression-coated tablet which is not subject to excessive deterioration of the active in: gredients and is pharmaceutically acceptable judged by the criteria of elegance and size, it is preferred to maintain the moisture content of the ultimate compression-coated tablet below a specified percent. The practical manufac turing methods of granulating, mixing, and compressing are such that the introduction of excessive moisture is an ever-present danger. Consequently, precautions to main tain low relative humidity atmospheric conditions are pre ferred and ingredients relatively free from moisture are preferred.

The experimental results showed that a moisture con tent per ultimate tablet of less than about 0.9 percent prevented excessive deterioration of the active ingredients including the adrenocortical steroid hormone which formed an etioacid degradation product.

It is to be understood that the invention is not to be limited to the exact details of operation or exact composiions shown and described herein, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. A medicinal tablet comprising a compression-coated outer layer containing a non-toxic member selected from the group consisting of acetylsalicylic acid and a compound convertible to acetylsalicylic acid on hydrolysis and an inner core reciprocally bonded to said outer layer containing a mixture of an anti-inflammatory adrenocoh tical steroid and calcium carbonate. 1

2. A medicinal tablet comprising a compression-coated outer layer containing a non-toxic member selected from the group consisting of acetylsalicylic acid and a compound yielding acetylsalicylic acid on hydrolysis and an inner core reciprocally bonded to said outer layer containing a mixture of calcium carbonate and a member selected from the group consisting of cortisone, hydrocortisone, prednisone, prednisolone, 6-methyl-prednisolone, 6-fluoro-hydrocortisone, 6-fluoro-prednisolone and the therapeutically active derivatives thereof.

3. A medicinal tablet comprising a compression-coated outer layer containing acetylsalicylic acid and an inner core reciprocally bonded to said outer layer containing a mixture of prednisolone and calcium carbonate.

4. The tablet of claim 3 in which [acetylsalicylic acid]- anhydride is substituted for the acetylsalicylic acid. 5. A medicinal tablet comprising a compression-coated outer layer containing from about 200 to about 400 milligrams of acetylsalicylic acid and an inner core recipro-' cally bonded to said outer layer containing a mixture of from about 0.25 to about 5.0 milligrams of prednisolone and an amount of calcium carbonate about milligrams in excess of the amount equirnolar with said acetyl-' salicylic acid.

6. A medicinal tablet comprising a compression-coated outer layer containing about 300 milligrams of a member selected from the group consisting of acetylsalicylic acid and [acetylsalicylic acidl-anhydride and an inner core aeaassa reciprocally bonded to said outer layer containing a mix ture of about 1.5 milligrams of prednisolone and about 200 milligrams of calcium carbonate.

7. A medicinal tablet comprising a compression-coated outer layer containing a member selected from the group consisting of acetylsalicylic acid and [acetylsalicylic acidl-anhydride and an inner core reciprocally bonded to said outer layer containing a mixture of an adrenocortical steroid and calcium carbonate, the moisture content of said tablet being less than about 0.9 percent by weight.

8. A medicinal tablet comprising a compression-coated outer layer containing about 300 milligrams of acetylsalicylic acid and an inner core reciprocally bonded to said outer layer containing a mixture of about 0.5 milligram of prednisolone and about 200 milligrams of calcium carbonate, the moisture content of said tablet being less than about 0.9 percent by weight.

9. A medicinal tablet comprising a compression-coated outer layer containing about 300 milligrams of acetylsalicylic acid and an inner core reciprocally bonded to said outer layer containing a mixture of about 0.35 milligram of o-methyl-prednisolone and about 200 milligrams of calcium carbonate, the moisture content of said tablet being less than about 0.9 percent by weight.

10. A medicinal tablet comprising a compressioncoated outer layer containing about 300 milligrams of [acetylsalicylic acidl-anhydride and an inner core reciprocally bonded to said outer layer containing a mixture of about 1.0 milligram of 6-methyl-prednisolone and about 200 milligrams of calcium carbonate, the moisture content of said tablet being less than about 0.9 percent by weight.

11. The process of preparing a compression-coated tablet containing an adrenocortical steroid, calcium carbonate and a non-toxic member selected from the group consisting of acetylsalicylic acid and a compound capable of yielding acetylsalicylic acid on hydrolysis which process comprises mixing an adrenocortical steroid with a granulation of calcium carbonate, compressing the said steroid-calcium carbonate mixture to form a core section, and compression-coating a reciprocally bonded layer of said non-toxic member on said core section.

12. The process of claim 11 characterized in that said process is carried out under a low relative humidity and with ingredients sufliciently dry to produce a tablet having a moisture content of less than about 0.9 percent by weight.

References Cited in the file of this patent UNITED STATES PATENTS 2,757,124 Wolff July 31, 1956 2,768,115 Buckwalter Oct. 23, 1956 OTHER REFERENCES Merck Index, 6th ed., Merck and Co., Rahway, N.I., 1952, p. 184.

Modern Drugs, January 1956, page 536 (Cortex).

Physicians Desk Ref., 11th ed., Med. Econ., Inc., Oradell, N.J., 1956, page 591 (Cordex). 

1. A MDEICINAL TABLET COMPRISING A COMPRESSION-COATED OUTER LAYER CONTAINING A NON-TOXIC MEMBER SELECTED FROM THE GROUP CONSISTING OF ACETYLSALICYLIC ACID AND A COMPOUND CONVERTIBLE TO ACETYLSALICYCLIC ACID ON HYDROLYSIS AND AN INNER CORE RECIPROCALLY BONDED TO SAID OUTER LAYER CONTAINING A MIXTURE OF AN ANTI-INFLAMMATORY ADRENOCORTICLA STEROID AND CALCIUM CARBONATE. 